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Considered an inflammatory disease, T2D predisposes to periodontitis by increasing whole\u2010body inflammation. One mechanism of increased inflammation is thatT2D is mediated by loss of production or function of the anti\u2010inflammatory hormone adiponectin. In our previous report, AdipoRon, an adiponectin receptor agonist, and AdipoAI, a newly discovered, more specific agonist, attenuated T2D\u2010associated inflammation by inhibiting osteoclastogenesis and LPS\u2010induced endotoxemia. Autophagy plays an important role during osteoclast differentiation and function. The impact of AdipoAI on osteoclast function and autophagy involved in osteoclastogenesis is not known. Here, we compare AdipoRon and AdipoAI potency, side effects and mechanism of action in T2D\u2010associated periodontitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The RAW 264.7 cell line was used for <jats:italic>in vitro<\/jats:italic> studies. We analyzed the potential cytotoxicity of AdipoAI using the CCK\u20108 assay. The anti\u2010osteoclastogenic potential of AdipoAI was studied by real\u2010time qPCR and tartrate\u2010resistant acid phosphatase staining. The actions of AdipoAI involved in autophagy were tested by real\u2010time qPCR, western blot and immunofluorescence staining. In the diet\u2010induced obesity model of T2D, we investigated the impact of AdipoAI on fasting blood glucose, alveolar bone loss, and gingival inflammation in mice with experimental periodontitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>AdipoRon inhibited osteoclastogenesis and AdipoAI inhibited osteoclastogenesis at lower doses than AdipoRon without any cytotoxicity. In DIO mice with experimental periodontitis, AdipoAI reduced mouse body weight in 14\u00a0days, reducing fasting glucose levels, alveolar bone destruction, osteoclast number along the alveolar bone surface, and decreased the expression of pro\u2010inflammatory factors in periodontal tissues. AdipoAI and AdipoRon also enhanced LC3A\/B expression when cultured with RANKL.3\u2011Methyladenine, a known autophagy inhibitor, decreased LC3A\/B expression and reversed the inhibition of osteoclastogenesis during AdipoAI treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate that AdipoAI ameliorates the severity of T2D\u2010associated periodontitis by enhancing autophagy in osteoclasts at lower doses than AdipoRon without demonstrable side effects. Thus, AdipoAI has pharmaceutical potential for treating diabetes\u2010associated periodontal disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.12969","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T05:48:18Z","timestamp":1641361698000},"page":"381-391","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A novel adiponectin receptor agonist (AdipoAI) ameliorates type 2 diabetes\u2010associated periodontitis by enhancing autophagy in osteoclasts."],"prefix":"10.1111","volume":"57","author":[{"given":"Xingwen","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Dentistry Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Division of Oral Biology Tufts University School of Dental Medicine  Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Dentistry Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renjie","family":"Cui","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine Ministry of Education Department of Biochemistry and Molecular Biology Collaborative Innovation Center of Genetics and Development Institutes of Biomedical Sciences School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Qiu","sequence":"additional","affiliation":[{"name":"Division of Oral Biology Tufts University School of Dental Medicine  Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine Ministry of Education Department of Biochemistry and Molecular Biology Collaborative Innovation Center of Genetics and Development Institutes of Biomedical Sciences School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhekai","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Oral Biology Tufts University School of Dental Medicine  Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Dentistry Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Dentistry Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duan","family":"Ma","sequence":"additional","affiliation":[{"name":"Key Laboratory of Metabolism and Molecular Medicine Ministry of Education Department of Biochemistry and Molecular Biology Collaborative Innovation Center of Genetics and Development Institutes of Biomedical Sciences School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Van Dyke","sequence":"additional","affiliation":[{"name":"Clinical and Translational Research Forsyth Institute Cambridge, Oral Medicine, Infection, and Immunity Harvard School of Dental Medicine  Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-8761","authenticated-orcid":false,"given":"Qisheng","family":"Tu","sequence":"additional","affiliation":[{"name":"Division of Oral Biology Tufts University School of Dental Medicine  Boston USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youcheng","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Dentistry Zhongshan Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dentistry Zhongshan Hospital Fudan University  Shanghai China"},{"name":"Department of Developmental Molecular and Chemical Biology Tufts University School of Medicine. 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